Ancient War of the World Within: Study Finds Anti-HIV Protein Evolved Millions of Years Before the Emergence of AIDS

SEATTLE — Jul. 29, 2004 — A protein that the body uses to attack the AIDS virus is actually a stealthy defense mechanism that evolved 32 million years before the emergence of HIV, according to new findings from Fred Hutchinson Cancer Research Center.

The research, by Harmit Malik, Ph.D., and colleagues in Fred Hutchinson's Basic Sciences Division, is available on the Public Library of Science Web site and will appear in the journal's September print edition.

The work hinges on a recently discovered protein called Apobec3G, which has been generating some buzz in the scientific community for its potential in shedding light on the genetic mechanisms of HIV prevention. The protein defends cells from HIV infection by causing mutations in the genetic material within the virus. In response, HIV produces a protein that binds to Apobec3G and targets it for destruction.

Such conflicts, often dubbed "genetic arms races," typically put pressure on both sparring partners to continually evolve new ways to outsmart and overcome each other just to stay in the game. Such genetic tugs of war also exemplify what is known among evolutionary biologists as the Red Queen Principle, a phrase borrowed from the Red Queen in Louis Carroll's "Through the Looking Glass" that refers to the paradox of running as fast as you can just to stay in place.

When comparing human Apobec3G genes with those of man's distantly related primate relatives, Malik and colleagues found, to their surprise, that the protein began to evolve in response to such Darwinistic pressure more than 30 million years before HIV-like viruses first infected primates, an event that occurred about a million years ago.

"This suggests that HIV is a newcomer to this conflict," Malik said, "because the host can't evolve a completely new defense in such a short period of time."

The discovery of Apobec3G's continual evolution — the result of the first detailed glimpse into the workings of a genome-defense system in which both parties to the conflict have been clearly identified — suggests that some forms of the protein are more effective at overcoming HIV infection than others, which may influence whether a person's disease advances rapidly, said Michael Emerman, Ph.D., an HIV researcher in the center's Human Biology and Basic Sciences divisions and a co-author of the study.

"There is great variation in disease progression among HIV-infected individuals," he said. "This variability is influenced by the type of virus that infects a person as well as by the person's genetic makeup. Increasingly, human genes are being discovered that influence viral progression. Apobec3G is a good candidate to be one of these genes."

The findings are a striking example of what can be learned from studying rapidly evolving proteins, the research approach taken by Malik's lab. Conflicts in nature drive this type of evolutionary change when two competing biological interests come head to head. Predators and prey often influence the evolution of one another, and the same can happen between viruses and proteins of the cells they infect.

"We don't always know what the conflict is, but by looking for proteins that are rapidly evolving in response to selective pressures we can identify candidates that participate in conflict," Malik said. "Some of them will be relevant to disease."

To identify the selective pressure on Apobec3G evolution, Sawyer and colleagues analyzed the genes from 12 primates — New World monkeys, Old World monkeys, great apes and humans — spanning 33 million years of evolution. This approach allowed them to backtrack through evolution and identify recent genetic changes a well as construct a hypothetical ancestor of all the species.

Most of the primates they examined showed evidence of what is known as positive selection, indicating that the gene has been under pressure to evolve throughout history. But lentiviruses — the family of viruses to which HIV belongs — have been found in only some of the primates studied and appear to be at most 1 million years old.

"What is novel about our findings is that scientists tend to study evolution of viruses but not the host proteins that work against them," said lead author Sara Sawyer, Ph.D., a postdoctoral-research fellow in Malik's lab.

"Based on how rapidly HIV changes, we assumed that we could learn something by focusing on Apobec3G," she said.

Sawyer and colleagues propose that Apobec3G's original enemy is a family of virus-like invaders of the genome called retrotransposons. Known as mobile genetic elements, these snippets of DNA are thought to be relics of ancient viral infections that insert themselves into many places in the genome, regardless of whether they may disrupt the genes that inhabit those locations. HIV and other lentiviruses are similar to these ancient genetic attackers in that they also insert themselves into the host genome after infection.

The researchers conducted a similar analysis of other mutation-inducing proteins closely related to Apobec3G and found that some of them also show signs of evolutionary pressure. These too may have arisen to defend the host genome against mobile genetic elements and may now play a role in defending against as-yet-unknown viruses.

Malik said that there is a good lesson to be learned from his lab's research approach.

"If you study what most people consider harmless oddities of the genome and host defenses against them, you may uncover some very interesting aspects of human disease."

The research was supported by funds from Fred Hutchinson Cancer Research Center and the National Institutes of Health.

Fred Hutchinson Cancer Research Center
The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Fred Hutchinson receives more funding from the National Institutes of Health than any other independent U.S. research center. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson, in collaboration with its clinical and research partners, the University of Washington Academic Medical Center and Children's Hospital and Regional Medical Center, is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 38 nationwide. For more information, visit the center's Web site at www.fhcrc.org.